Medical device for delivering a therapeutic agent and method of preparation

ABSTRACT

A device useful for localized delivery of a therapeutic agent is provided. The device includes a structure including a porous polymeric material and an elutable therapeutic agent in the form of a solid, gel, or neat liquid, which is dispersed in at least a portion of the porous polymeric material. Methods for making a medical device having a blood-contacting surface is also provided. One method involves: providing a structure comprising a porous material; contacting the structure comprising a porous material with a concentrating agent to disperse the concentrating agent throughout at least a portion of the porous material; contacting the structure comprising a porous material and the concentrating agent with a solution of a therapeutic agent; and removing the therapeutic agent from solution within the porous material at the locations of the concentrating agent. Another method involves multiple immersion steps without the use of a concentrating agent.

BACKGROUND OF THE INVENTION

[0001] This invention relates to a medical device employing atherapeutic agent as a component thereof. For example, in an arterialsite treated with percutaneous transluminal coronary angioplasty therapyfor obstructive coronary artery disease a therapeutic antithrombogenicsubstance such as heparin may be included with a device and deliveredlocally in the coronary artery. Also provided is a method for making amedical device capable of localized application of therapeutic agents.

[0002] Medical devices which serve as substitute blood vessels,synthetic and intraocular lenses, electrodes, catheters, and the like,in and on the body, or as extracorporeal devices intended to beconnected to the body to assist in surgery or dialysis are well known.For example, intravascular procedures can bring medical devices intocontact with the patient's vasculature. In treating a narrowing orconstriction of a duct or canal percutaneous transluminal coronaryangioplasty (PTCA) is often used with the insertion and inflation of aballoon catheter into a stenotic vessel. Other intravascular invasivetherapies include atherectomy (mechanical systems to remove plaqueresiding inside an artery), laser ablative therapy, and the like.However, this use of mechanical repairs can have adverse consequencesfor the patient. For example, restenosis at the site of a prior invasivecoronary artery disease therapy can occur. Restenosis, definedangiographically, is the recurrence of a 50% or greater narrowing of aluminal diameter at the site of a prior coronary artery disease therapy,such as a balloon dilatation in the case of PTCA therapy. In particular,an intra-luminal component of restenosis develops near the end of thehealing process initiated by vascular injury, which then contributes tothe narrowing of the luminal diameter. This phenomenon is sometimesreferred to as “intimal hyperplasia.” It is believed that a variety ofbiologic factors are involved in restenosis, such as the extent of theinjury, platelets, inflammatory cells, growth factors, cytokines,endothelial cells, smooth muscle cells, and extracellular matrixproduction, to name a few.

[0003] Attempts to inhibit or diminish restenosis often includeadditional interventions such as the use of intravascular stents and theintravascular administration of pharmacological therapeutic agents.Examples of stents which have been successfully applied over a PTCAballoon and radially expanded at the same time as the balloon expansionof an affected artery include the stents disclosed in U.S. Pat. No.4,733,665 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), and U.S. Pat.No. 4,886,062 (Wiktor).

[0004] Also, such stents employing therapeutic agents such asglucocorticoids (e.g. dexamethasone, beclamethasone), heparin, hirudin,tocopherol, angiopeptin, aspirin, ACE inhibitors, growth factors,oligonucleotides, and, more generally, antiplatelet agents,anticoagulant agents, antimitotic agents, antioxidants, antimetaboliteagents, and anti-inflammatory agents have been considered for theirpotential to solve the problem of restenosis. Such substances have beenincorporated into (or onto) stents by a variety of mechanisms. Thesemechanisms involve incorporating the therapeutic agents into polymericcoatings and films, including hydrogels, as well as covalently bindingthe therapeutic agents to the surface of the stent.

[0005] For example, therapeutic agents have been dissolved or dispersedin a solution of polymer in an organic solvent. This is then sprayedonto the stent and allowed to dry. Alternatively, therapeutic agentshave been incorporated into a solid composite with a polymer in anadherent layer on a stent body with fibrin in a separate adherent layeron the composite to form a two layer system. The fibrin is optionallyincorporated into a porous polymer layer in this two layer system. Thetherapeutic agent, however, is incorporated into the underlying solidpolymer. The overlying porous polymer layer provides a porous barrierthrough which the therapeutic agent is transferred.

[0006] Conventional methods of loading the therapeutic agent into apolymer, such as spray coating, do not provide high concentrations oftherapeutic agents. Typically, upon spray coating a therapeutic agentonto a stent body, only about 2 percent of the spray is captured by thestent. This can be prohibitively expensive for therapeutic agents thatare extremely costly and scarce, such as peptidic drugs.

[0007] Thus, what is needed is a medical device, preferably, a stent,having a porous polymeric material, typically a polymer layer in theform of a coating or film, with a therapeutic agent incorporated thereinat sufficiently high concentrations that the therapeutic agent can bedelivered over an extended period of time. Improved methods by which thetherapeutic agent can be incorporated into the porous polymeric materialwith lower levels of waste are also needed.

SUMMARY OF THE INVENTION

[0008] This invention relates to a medical device having a porouspolymeric material with a therapeutic agent therein. Preferably, thedevice according to the invention is capable of applying a highlylocalized therapeutic agent into a body lumen to treat or preventinjury. The term “injury” means a trauma, that may be incidental tosurgery or other treatment methods including deployment of a stent, or abiologic disease, such as an immune response or cell proliferationcaused by the administration of growth factors. In addition, the methodsof the invention may be performed in anticipation of “injury” as aprophylactic. A prophylactic treatment is one that is provided inadvance of any symptom of injury in order to prevent injury, preventprogression of injury or attenuate any subsequent onset of a symptom ofsuch injury.

[0009] In accordance with the invention, a device for delivery oflocalized therapeutic agent includes a structure including a porousmaterial and an elutable (i.e., capable of being dissolved underphysiological conditions) therapeutic agent in the form of a solid, gel,or neat liquid, which is dispersed throughout at least a portion, andpreferably a substantial portion, of the porous material. Preferably,the device is capable of being implanted in a body so that the localizedtherapeutic agent can be delivered in vivo, typically at a site ofvascular injury or trauma. Preferably, the porous material isbiocompatible, sufficiently tear-resistant, and non-thrombogenic.

[0010] The porous material may be a layer (e.g., a film, i.e., a sheetmaterial or a coating) on at least a portion of the structure.Alternatively, the porous material may be an integral portion of thestructure. Preferably, the porous material is a polymeric materialselected from the group of a natural hydrogel, a synthetic hydrogel,silicone, polyurethane, polysulfone, cellulose, polyethylene,polypropylene, polyamide, polyester, polytetrafluoroethylene, and acombination of two or more of these materials. Examples of naturalhydrogels include fibrin, collagen, elastin, and the like. Morepreferably, the porous polymeric material is a nonswelling biostablepolymer selected from the group of silicone, i polyurethane,polysulfone, cellulose, polyethylene, polypropylene, polyamide,polyester, polytetrafluoroethylene, and a combination of two or more ofthese materials.

[0011] The therapeutic agent can be one or more of a wide variety oftherapeutic agents, including peptidic drugs. Preferably, thetherapeutic agent includes an antithrombotic material. More preferably,the antithrombotic material is a heparin or heparin derivative oranalog. Such therapeutic agents are soluble in water such that theyelute from the porous polymeric material.

[0012] The structure of the device can be adapted for its intendedextracorporeal or intravascular purpose in an internal human body site,such as an artery, vein, urethra, other body lumens, cavities, and thelike or in an extracorporeal blood pump, blood filter, blood oxygenatoror tubing. In one aspect of the invention, the shape is preferablygenerally cylindrical, and more preferably, the shape is that of acatheter, a stent, or a guide wire. In particularly preferredembodiments, the medical device is an intralumenal stent.

[0013] The invention also provides methods for making a medical devicewhich includes therapeutic agents. In one embodiment, a method of theinvention includes: providing a structure comprising a porous material;contacting the structure comprising a porous material with aconcentrating agent to disperse the concentrating agent throughout atleast a portion of the porous material; contacting the structurecomprising a porous material and the concentrating agent with a solutionof a therapeutic agent; and removing the therapeutic agent from solutionwithin the porous material at the locations of the concentrating agent.

[0014] The present invention also provides a method for making a medicaldevice that includes: providing a structure comprising a porousmaterial; immersing the structure comprising a porous material in asaturated solution of a therapeutic agent for a sufficient period oftime to allow the solution to fill the porous material; removing themedical device from the solution; drying the medical device; andrepeating the steps of immersing, removing, and drying to provide atherapeutic agent dispersed within the porous material. Preferably, themethod further includes a step of removing air bubbles from the porousmaterial while being immersed in the solution of the therapeutic agent.The step of removing air bubbles from the porous material can includeapplying ultrasonics, reduced pressure, elevated pressure, or acombination thereof, to the solution. Preferably, the method involvesloading a stent having a porous polymeric film thereon, and subsequentlyapplying an overlayer of a polymer.

[0015] A therapeutic agent may be loaded onto a structure including aporous material at any number of points between, and including, thepoint of manufacture and the point of use. For example, the device canbe stored and transported prior to incorporation of the therapeuticagent. Thus, the end user can select the therapeutic agent to be usedfrom a wider range of therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 is an elevational view of one embodiment of a deviceaccording to the invention with a balloon catheter as a mode of deliveryof the device; and

[0017]FIG. 2 is an elevational view of another embodiment of a deviceaccording to the invention with a balloon catheter as a mode of deliveryof the device.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0018] One of the more preferred configurations for a device accordingto the invention is a stent for use in artery/vascular therapies. Theterm “stent” refers to any device capable of being delivered by acatheter and which, when placed into contact with a portion of a wall ofa lumen to be treated, will also deliver localized therapeutic agent ata luminal or blood-contacting portion of the device. A stent typicallyincludes a lumen wall-contacting surface and a lumen-exposed surface.Where the stent is shaped generally cylindrical or tube-like, includinga discontinuous tube or ring-like structure, the lumen-wall contactingsurface is the surface in close proximity to the lumen wall whereas thelumen-exposed surface is the inner surface of the cylindrical stent. Thestent can include polymeric or metallic elements, or combinationsthereof, onto which a porous material is applied. For example, adeformable metal wire stent is useful as a stent framework of thisinvention, such as that described in U.S. Pat. No. 4,886,062 (Wiktor),which discloses preferred methods for making a wire stent. Othermetallic stents useful in this invention include those of U.S. Pat. No.4,733,655 (Palmaz) and U.S. Pat. No. 4,800,882 (Gianturco).

[0019] Other medical devices, such as heart valves, vascular grafts,pacing leads, etc., can also include the embodiments of the presentinvention. As used herein, medical device refers to a device that hassurfaces that contact tissue, blood, or other bodily fluids in thecourse of their operation, which fluids are subsequently used inpatients. This can include, for example, extracorporeal devices for usein surgery such as blood oxygenators, blood pumps, blood sensors, tubingused to carry blood and the like which contact blood which is thenreturned to the patient. This can also include endoprostheses implantedin blood contact in a human or animal body such as vascular grafts,stents, pacemaker leads, heart valves, and the like that are implantedin blood vessels or in the heart. This can also include devices fortemporary intravascular use such as catheters, guide wires, and the likewhich are placed into the blood vessels or the heart for purposes ofmonitoring or repair.

[0020] Referring now to FIG. 1, the stent 20 comprises a stent framework22 and a porous material coating 24. The stent framework 22 isdeformable and can be formed from a polymeric material, a metal, or acombination thereof. A balloon 15 is positioned in FIG. 1 adjacent thelumen-exposed surface of the stent to facilitate delivery of the stent.

[0021] The stent 20 can be modified to increase or to decrease thenumber of wires provided per centimeter in the stent framework 22.Similarly, the number of wire turns per centimeter can also be modifiedto produce a stiffer or a more flexible stent framework.

[0022] Polymeric stents can also be used in this invention. The polymerscan be nonbioabsorbable or bioabsorbable in part, or total. Stents ofthis invention can be completely nonbioabsorbable, totally bioabsorbableor a composite of bioabsorbable polymer and nonabsorbable metal orpolymer. For example, another stent suitable for this invention includesthe self-expanding stent of resilient polymeric material as disclosed inInternational Publication No. WO 91/12779 (Medtronic, Inc.).

[0023] Nonbioabsorbable polymers can be used as alternatives to metallicstents. The stents of this invention should not substantially induceinflammatory and neointimal responses. Examples of biostablenonabsorbable polymers that have been used for stent construction withor without metallic elements include polyethylene terephthalate (PET),polyurethane urea, and silicone. Although the porous material is shownas a coating 24, it is to be understood that, for the purposes of thisinvention, the porous material can be incorporated into the material ofthe stent.

[0024] Referring to FIG. 2, an alternative stent 30 is shown. The stentframework 34 is affixed with a film of a porous material 32. This can beaccomplished by wrapping the film 32 around the stent framework 34 andsecuring the film 32 to the framework 34 (i.e., the film is usuallysufficiently tacky to adhere itself to the framework but a medical gradeadhesive could also be used if needed) so that the film 32 will stay onthe balloon 36 and framework 34 until it is delivered to the site oftreatment. The film 32 is preferably wrapped over the framework withfolds or wrinkles that will allow the stent 30 to be readily expandedinto contact with the wall of the lumen to be treated. Alternatively,the film 32 can be molded to the stent framework 34 such that theframework 34 is embedded within the film 32. Preferably, the film 32 islocated on a lumen-wall contacting surface 33 of the stent framework 34such that therapeutic material is substantially locally delivered to alumen wall, for example, an arterial wall membrane (not shown).

[0025] Porous Material

[0026] As mentioned above, the device according to the invention isgenerally a structure including a porous material. In one embodiment,the porous material includes a polymeric film or coating on at least aportion of the structure. In another embodiment, the porous material isan integral portion of the structure. Preferably, the porous material isa biocompatible polymer and is sufficiently tear-resistant andnonthrombogenic. Examples of suitable polymers are disclosed in U.S.Pat. No. 5,679,400 (Tuch). More preferably, the porous material isselected from the group of a natural hydrogel, a synthetic hydrogel,silicone, polyurethane, polysulfone, cellulose, polyethylene,polypropylene, polyamide, polyester, polytetrafluoroethylene, and acombination of two or more of these materials. Examples of naturalhydrogels include fibrin, collagen, elastin, and the like. In materialswhich do not include pores in their usual structural configurations,pores of about 10 micrometers in diameter or as large as 1000micrometers in diameter can be introduced by conventional means such asby introducing a solvent soluble particulate material into the desiredstructure and dissolving the particulate material with a solvent.

[0027] Typically, and preferably, the porous material is in the form ofa sheet material or coating of a nonswelling biostable polymer. As usedherein, a “nonswelling biostable” or “nonswellable biostable” polymer isone that does not absorb a significant amount of water (i.e., it absorbsless than about 10 weight percent water) and it is not readily degradedin the body. Such nonswelling biostable polymers include, for example,silicone, polyurethane, polysulfone, cellulose, polyethylene,polypropylene, polyamide, polyester, polytetrafluoroethylene, andcombinations thereof. If the polymer is biodegradable, the rate at whichit degrades is slower than the rate at which the therapeutic agentelutes.

[0028] If the porous material is in the form of a porous sheet (i.e.,film) or coating, it can be made by a variety of methods. These methodscan include, for example, using a solid particulate material (alsoreferred to herein as pore-forming material) that can be substantiallyremoved after the film or coating is formed, thereby forming pores. Byusing a solid particulate material during film or coating formation, thesize of the pores can, to some extent, be controlled by the size of thesolid particulate material being used. The particulate material canrange from less than about 1 micrometer in diameter to about 1000micrometers, preferably about 1 micrometer to about 100 micrometers,more preferably about 5 micrometers to about 50 micrometers. Foruniformity of pores, the particulate material can be screened throughsuccessively finer mesh sieves, e.g., through 100, 170, 270, 325, 400,and 500 mesh analytical grade stainless steel mesh sieves, to produce adesired range of particle sizes.

[0029] The particulate material may include inorganic and organicparticulate material, including, for example, sodium chloride, lithiumchloride, sucrose, glucose, sorbitol, sodium citrate, sodium ascorbate,urea, citric acid, dextran, poly(ethylene glycol), sodium nitroprusside,mannitol, sodium bicarbonate, ascorbic acid, sodium salicylate, orcombinations thereof. It will be understood by one of skill in the artthat a mixture of different particulate materials can be used ifdesired. Also, it will be understood by one of skill in the art thatbecause a portion of the particulate material may remain within thefilm, it is preferred that the solid particulate material bebiocompatible.

[0030] Typically, the particulate material chosen is less soluble thanthe polymer in the chosen solvent (e.g., water or an organic solvent)used to deposit or form the polymer. The particulate material mayactually be soluble in the solvent; however, to form pores, it only hasto be less soluble than the polymer in the solvent of choice. As thesolvent is removed from the solution, the pore-forming material willprecipitate out of solution and form particles surrounded by thepolymer, which is still in solution. The polymer then will come out ofsolution as more solvent is removed and the particles will be dispersedwithin the polymer. After the solvent is removed, the particulatematerial is removed using a liquid in which the polymer is not soluble,thereby forming pores.

[0031] In one method according to the present invention, a porous sheetmaterial (e.g., polyurethane sheet material) can be made by dissolving apolymer (e.g., polyether urethane) in an organic solvent (e.g.,1-methyl-2-pyrrolidone); mixing into the resulting polymer solution acrystalline, particulate material (e.g., sodium chloride, sucrose, etc.)that is not soluble in the solvent; casting the solution withparticulate material into a thin film; and then applying a secondsolvent (e.g., water), to dissolve and remove the particulate material,thereby leaving a porous sheet. Such a method is disclosed in U.S. Pat.No. 5,591,227 (Dinh et al.) and U.S. Pat. No. 5,599,352 (Dinh et al.).

[0032] Preferably, a combination of soluble and insoluble particulatematerial may be used to create a broader range of pore sizes. The use ofa soluble particulate material, such as poly(ethylene glycol), maycreate small (<2 μm diameter) interconnecting pores that create asolvent path for the removal of the larger (e.g., 50 μm) particles,which may not be in particle-to-particle contact.

[0033] A suspension of particulate material may be created by firstdissolving the particulate in a solvent, then precipitating the mixturein a solution of polymer in a second solvent in which the particulate isinsoluble. For example, an 8% solution of sodium nitroprusside inethanol can be added with rapid stirring to a 2% solution ofpolyurethane in tetrahydrofuran. The sodium nitroprusside precipitatesto form a suspension of less than about 5 μm particles.

[0034] The weight ratio of pore-forming material to polymer in a coatingcomposition may range from about 1:3 to about 9:1, preferably, about 2:1to about 9:1, although this is not necessarily limiting. In theory, theporosity is limited by the toughness of the polymer.

[0035] A smooth coating may be obtained by applying an atomized spray tothe stent. The spray should be applied at a rate such that evaporationprevents the accumulation of sufficient liquid to form drips along thestent. A macroscopically smooth surface may also be obtained by keepingthe particle size less than about % of the coating or film thickness.

[0036] Although films (i.e., sheet materials) for medical devices,particularly stent bodies, according to the present invention can bemanufactured separately from the support structure of the medical deviceand attached to the support structure after formation, preferred methodsinclude forming the films directly on the support structure sucl thatthe support structure is at least partially, preferably completely,encapsulated by the film (i.e., sheet material).

[0037] Alternatively, medical devices can include a coating of a porouspolymer made by spraying a solution of the polymer and particulatematerial directly on the support. In this way, the coating does notnecessarily form a film that encapsulates the device; rather it forms acoating around the structure (e.g., wire) of the device. The geometry ofthe porous material (coated wires vs. sheets or films) depends on thecoating substrate and is largely independent of the pore forming andapplication methods used. A film can be made by spraying, dipping, orcasting, as long as the mandrel is a rod or a flat sheet. The stentwires can be coated by any of these methods as well, although mostpreferably, they are coated by spraying to prevent droplet formation.

[0038] In one such method, which is disclosed in InternationalPublication No. WO 97/07973 (Medtronic, Inc.), a stent is placed on amandrel. A particulate material is then applied to the mandrel and stentsuch that it is lightly adhered to the mandrel. The particulate materialshould be readily soluble in a solvent which will not also dissolve thepolymer chosen for the film. For example, crystalline sodium bicarbonateis a water soluble material that can be used as the particulatematerial. A non-aqueous js liquid, preferably a solvent for the polymerfilm material, can be applied to the mandrel before applying theparticulate material in order to retain more of the particulate materialon the mandrel. For example, when a polyurethane is to be used for thefilm material, the solvent 1-methyl-2-pyrrolidinone (NMP) can be used towet the surface of the mandrel before the application of particulatematerial. Preferably, the mandrel is completely dusted with theparticulate in the portions of the mandrel to be coated with the polymerfilm. This can be accomplished by dipping the mandrel in NMP, allowingit to drain vertically for a few seconds and then dusting the sodiumbicarbonate onto the mandrel while rotating it horizontally until nofurther bicarbonate particles adhere. Excess particulate material can beremoved by gently tapping the mandrel.

[0039] Coating with polymer may proceed immediately followingapplication of the particulate material. A polymer is provided in adilute solution and is applied to the particle-coated stent and mandrel.For example, polyurethane can be dissolved in NMP to make a 10%solution. Gel particles and particulate impurities can be removed fromthe solution by use of a clinical centrifuge. The polymer solution canbe applied by dipping the mandrel into the solution and letting thesolvent evaporate. With the solution of polyurethane and NMP, a singledip in the solution can provide a film of adequate thickness. To assistin the formation of communicating passageways through the polymerbetween the blood-contacting surface and the lumen-contacting surface,additional sodium bicarbonate particles are preferably dusted onto thepolymer solution immediately after the dipping operation and before thepolymer solution has dried. Excess particulate material can be removedby gently tapping the mandrel. To precipitate and consolidate thepolyurethane film on the stent, it can be dipped briefly (about 5minutes) in water and then rolled gently against a wetted surface, suchas a wet paper towel. The stent assembly can then be placed into one ormore water baths over an extended period (e.g., 8 hours) to dissolve andremove the sodium bicarbonate. After drying in air at temperatures fromabout 20° C. to about 50° C., the film then can be trimmed to match thecontour of the .wire.

[0040] In yet another method, a solvent in which the polymer is solublethat is capable of phase separating from the polymer at a reducedtemperature can be used to prepare a porous polymer film. In thismethod, the stent or other medical device is placed in a cavity of amold designed for forming a film around the stent, similar to thatdisclosed in U.S. Pat. No. 5,510,077 (Dinh et al.). A solution of thedesired polymer, such as polyurethane, dissolved in a solvent, such asdioxane, is added to the mold. The temperature of the solution is thenreduced to a temperature at which the solvent freezes and phaseseparates from the polymer, thereby forming particulate material (i.e.,frozen solvent particles) in situ. Typically, for polyurethane indioxane, this is a temperature of about −70° C. to about 3° C. Thecomposition is then immersed in an ice cold water bath (at about 3° C.)for a few days to allot the dioxane to dissolve into the ice cold water,thereby forming pores. The number and size of the pores can becontrolled by the concentration of the polymer and the freezingtemperature. A method similar to this is disclosed in Liu et al., J.Biomed. Mater. Res., 26, 1489 (1992). This method can be improved on byusing a two-step freezing process as disclosed in U.S. patentapplication. Ser. No. ______,filed on Apr. 29, 1998 (Attorney Docket No.P-4242).

[0041] In yet another embodiment, a porous material can be created froma mixture of a low boiling good solvent and a higher boiling poorsolvent, in which the polymer is soluble. After application to thetarget substrate, the lower boiling good solvent evaporatespreferentially until a point is reached where the polymer precipitatesfrom the remaining solvent mixture, which is relatively richer in thepoor solvent. The polymer precipitates in and around pockets of the poorsolvent, creating a porous structure. The number and size of pores canbe controlled by the boiling points of the two solvents, theconcentration of polymer and the drying rate. An example is a 1%solution of poly(l-lactic acid) (PLLA) in a 60:40 mixture ofchloroform:iso-octane. As the chloroform evaporates, the PLLAprecipitates from the iso-octane to create an opague PLLA coatingcontaining 2-5 μm pores. This method is further described in U.S. Pat.No. 5,679,400 (Tuch).

[0042] Therapeutic Agent

[0043] The therapeutic agent used in the present invention could bevirtually any therapeutic agent which possesses desirable therapeuticcharacteristics and which can be provided in a form that can besolubilized, for example, by water or an organic solvent, and arecapable of being eluted from the porous polymeric material in the bodyof a patient. Preferred therapeutic agents are solids, gels, or neatliquids (i.e., materials not dissolved in a solvent) at room temperature(i.e., about 20-25° C.), and preferably at body temperatures, that arecapable of being eluted from the porous polymeric material in the bodyof a patient. For example, antithrombotics, antiplatelet agents,antimitotic agents, antioxidants, antimetabolite agents,anti-inflammatory agents, enzyme inhibitors, and anti-angiogenic factorsas disclosed in U.S. Pat. No. 5,716,981 (Hunter et al.) could be used.Anticoagulant agents, such as heparin, heparin derivatives, and heparinanalogs, could also be used to prevent the formation of blood clots onthe device.

[0044] Methods of Making an Implantable Device

[0045] A structure having a porous material, preferably a porouspolymeric material, can be loaded with one or more therapeutic agentsusing a wide variety of methods. For example, the porous material can beimmersed in a solution or dispersion of the therapeutic agent in asolvent. The solution (preferably, a supersaturated solution) ordispersion is allowed to fill the pores and the solvent is allowed toevaporate leaving the therapeutic agent dispersed within at least aportion of the pores. The solvent can be water or an organic solventthat does not dissolve the polymer. If the solvent does not dissolve thetherapeutic agent, the particles of the therapeutic agent are smallerthan the pore openings. Alternatively, in certain embodiments, thesolvent can be chosen such that it swells the polymer, thereby achievinga greater level of incorporation of the therapeutic agent.

[0046] The following methods for loading one or more therapeutic agentsinto porous material are improved over prior art methods, such as spraycoating methods. Although the same amount of therapeutic agent can beloaded onto a medical device, significantly less (e.g., about 100x less)waste of the therapeutic agent occurs using the following methods. Thisis particularly important for expensive therapeutic agents, such aspeptic drugs.

[0047] In one embodiment of the invention, filling of the pores can beenhanced through the use of ultrasonics, vacuum, and/or pressure. Whilethe device is submerged in solution, ultrasonic energy or vacuum can beused to accelerate the removal of air bubbles from the pores allowingthe pores to fill with the solution containing the therapeutic agent.Hyperbaric pressure on the solution may cause the air in the pores to bedissolved in the solution, thereby allowing the pores to fill withliquid. Furthermore, the level of incorporation can be increased byusing multiple dip-vacuum-dry cycles. If the therapeutic agentsaturates, the solution by 10% by volume, for example, when the solventevaporates the pores will be 10% filled with the agent. Repeating thecycle will fill the remaining 90% void space and fill an additional 9%of the original pore volume. Further cycles continue the trend. For thisprocedure to be effective, however, the solution is saturated so thatthe previously deposited agent does not dissolve in subsequent cycles.

[0048] Preferably, a method of the invention includes loading astructure comprising a porous material with a concentrating agent, whichmay be a precipitating agent (e.g., a binding agent, sequestering agent,nucleating agent, etc.), a seed crystal, or the like, dispersedthroughout at least a portion, preferably, a substantial portion, of theporous material, and subsequently loading the structure comprising aporous material and the concentrating agent with a solution of atherapeutic agent, wherein the therapeutic agent is removed fromsolution (e.g., as by crystallization and/or precipitation) within theporous material at the locations of the concentrating agent. This is asignificantly improved method in that the concentrating agent provides adriving force for localization of the drug within the pores of thepolymer. That is, it is believed that the concentrating agent provides athermodynamically favorable surface for crystallization orprecipitation.

[0049] The concentrating agent can be a precipitating agent or a seedcrystal, for example, or any substance that can cause the therapeuticagent to fall out of solution. As used herein, a seed crystal is a solidmaterial that is the same as the therapeutic agent being deposited. Asused herein, a precipitating agent is a solid material that is differentfrom the therapeutic agent being deposited. It can include, for example,materials that have a particular affinity for the therapeutic agent ofinterest, such as binding agents, sequestering agents, nucleatingagents, and mixtures thereof. Examples of sequestering agents includeheparin to sequester heparin binding growth factors such as bFGF and,for example, cyclodextrins to trap appropriately sized therapeuticagents to fit in their ring structures. Examples of binding agentsinclude polycations (e.g., protamine) and polyanions (e.g., heparinsulfate) for binding anionic and cationic therapeutic agents,respectively. The binding agent can also include a counterion of a saltthat is insoluble upon complexation with the therapeutic agent in thesolvent used in the solution of the therapeutic agent.

[0050] The solution containing the therapeutic agent is preferably asupersaturated solution, although this is not a necessary requirement.This can be prepared at elevated temperatures taking into considerationthe limits of stability of the therapeutic agents and the porousmaterial. The porous polymeric material with concentrating agent thereincan be Is immersed in a solution of the therapeutic agent in a solvent.The solution is allowed to fill the pores and the therapeutic agentallowed to come out of solution (e.g., as by the formation of crystals).The solvent can be water or an organic solvent that does not dissolvethe porous polymer, although it may swell the polymer as describedabove. The choice of solvent is one that is compatible with thetherapeutic agent and porous material of choice. Filling of the porescan be enhanced through the use of ultrasonics, vacuum, and/or pressure,as well as by using multiple dip-vacuum-dry cycles, as described above.

[0051] Crystal and/or precipitate formation can be initiated by avariety of mechanisms. They may spontaneously form. Alternatively, thesolution of the therapeutic agent within the pores may need to be cooledto initiate crystallization and/or precipitation. It may be possible toinitiate crystallization and/or precipitation by changing the pH and/orionic strength of the solution of the therapeutic agent within thepores.

[0052] The initial concentrating agent, which may be a solid, liquid, ora gel, can be placed in the pores of the porous material by a variety ofmethods. For example, if the concentrating agent is a seed crystal ofthe therapeutic agent of interest, immersing the porous material in asolution or dispersion of the therapeutic agent in a solvent, allowingit to fill the pores, and allowing the solvent to evaporate, providesthe therapeutic agent dispersed within at least a portion of the pores,as described above. Similarly, if the concentrating agent is aprecipitating agent, the porous material can be immersed in a solutionof this agent.

[0053] The methods of the present invention are advantageous in that thestructure can be loaded with the therapeutic agent in situ, i.e., at ornear the point of therapeutic use, typically before administration,preferably implantation, to a patient. This is particularly usefulbecause the device can be stored and transported prior to incorporationof the therapeutic agent. This feature has several advantages. Forexample, m the relevant consumer can select the therapeutic agent to beused from a wider range of therapeutic agents. Thus, the therapeuticagent selected is not limited to only those supplied with the device butcan instead be applied according to the therapy required.

[0054] In order to provide additional control over the elution of thetherapeutic agent, an overlayer may be applied to the medical device, asis disclosed in U.S. Pat. No. 5,679,400 (Tuch), U.S. Pat. No. 5,624,411(Tuch), and U.S. Pat. No. 5,624,411 (Tuch). The overlayer, typically inthe form of a porous polymer, is in intimate contact with thetherapeutic agent and allows it to be retained on the medical device. Italso controls the administration of the therapeutic agent followingimplantation. For a stent, an overlayer is particularly desirable toretain the therapeutic agent on the stent during expansion of the stent.

[0055] The following nonlimiting examples will further illustrate theinvention. All parts, percentages, ratios, etc. are by weight unlessotherwise indicated.

EXAMPLE

[0056] Wiktor stents were coated as follows: 4 grams of a 5 wt %solution of polyurethane as disclosed in U.S. Pat. No. 4,873,308 (Couryet al.) in tetrahydrofuran (THF) and 20 grams of a 5 wt % solution ofcitric acid in THF were combined and sprayed onto wiktor stents using anair brush, similar to the method disclosed in U.S. Pat. No. 5,679,400(Tuch). Citric acid was extracted with deionized water for 10 minutes.The stent was then air dried at ambient temperature and weighed. Theporous polyurethane coating weights were 0.5-0.7 mg.

[0057] Into a microcentrifuge tube was added 0.12 g tissue factorpathway inhibitor (TFPI) and 1.0 ml sterile water. This was agitated todissolve the TFPI. The polyurethane coated stents were immersed in theTFPI solution, which was subjected to reduced pressure (28 inches of Hg)to evacuate the air from the pores. The stents were air dried and theimmersion/vacuum process was repeated twice. After the last immersionprocess, stents were air dried at ambient temperature for 20 minutes.Each stent was immersed for less than two seconds in deionized water toremove TFPI on the surface of the stents. The stents were then dried inambient temperature under vacuum for about 12 hours. The stents wereweighed to determine the amount of TFPI loaded into the pores, whichranged from 0.15 mg to 0.33 mg.

[0058] Half the stents were overcoated with a 2 wt % solution ofpolyurethane solution in THF using the spray coating method describedabove, resulting in a coating weight of 0.6 mg. These stents were testedfor elution. The stents with the overcoating eluted more slowly than thestents without the overcoating.

[0059] The complete disclosures of all patents, patent applications, andpublications referenced herein are incorporated herein by reference asif individually incorporated. Various modifications and alterations ofthis invention will become apparent to those skilled in the art withoutdeparting from the scope and spirit of this invention, and it should beunderstood that this invention is not to be unduly limited toillustrative embodiments set forth herein.

We claim:
 1. A medical device having at least one blood-contactingsurface comprising: a porous polymeric material comprising anonswellable biostable polymer; and an elutable therapeutic agent in theform of a solid, gel, or neat liquid, which is dispersed in at least aportion of the porous polymeric material.
 2. The medical device of claim1 wherein the porous polymeric material comprises a film.
 3. The medicaldevice of claim 1 wherein the nonswellable biostable polymer is selectedfrom the group consisting of silicone, polyurethane, polysulfone,cellulose, polyethylene, polypropylene, polyamide, polyester,polytetrafluoroethylene, and a combination of two or more of thesematerials.
 4. The medical device of claim 3 wherein the porous polymericmaterial comprises an integral portion of the device.
 5. The medicaldevice of claim 1 wherein the therapeutic agent comprises anantithrombotic material.
 6. The medical device of claim 5 Wherein theantithrombotic material is heparin.
 7. The medical device of claim 1wherein the therapeutic agent is a peptic drug.
 8. The medical device ofclaim 1 wherein the device has a generally cylindrical shape.
 9. Thedevice of claim 8 wherein the device is selected from the groupconsisting of a catheter, a stent, and a guide wire.
 10. The device ofclaim 1 wherein the device has a generally sheet-like shape.
 11. Themedical device of claim 1 wherein the device is an intralumenal stent.12. An intralumenal stent comprising: a generally cylindrical stentbody; and and an adherent layer on the stent body comprising a porouspolymeric material and an elutable therapeutic agent in the form of asolid, gel, or neat liquid, which is dispersed in at least a portion ofthe porous polymeric material.
 13. A method for making a medical devicecomprising: (a) providing a structure comprising a porous material; (b)contacting the structure comprising a porous material with aconcentrating agent to disperse the concentrating agent throughout atleast a portion of the porous material; (c) contacting the structurecomprising a porous material and the concentrating agent with a solutionof a therapeutic agent; and (d) removing the therapeutic agent fromsolution within the porous material at the locations of theconcentrating agent.
 14. The method of claim 13 wherein precipitatingagent is selected from the group of a binding agent, sequestering agent,a nucleating agent, a seed crystal, or combinations thereof.
 15. Themethod of claim 13 wherein the porous material is selected from thegroup consisting of a natural hydrogel, a synthetic hydrogel, silicone,polyurethane, polysulfone, cellulose, polyethylene, polypropylene,polyamide, polyester, polytetrafluoroethylene, and a combination of twoor more of these materials.
 16. The method of claim 13 wherein thetherapeutic agent is an antithrombotic material.
 17. The method of claim13 wherein the step of removing the therapeutic agent from solutioncomprises reducing the temperature of the solution of the therapeuticagent.
 18. The method of claim 13 wherein the step of removing thetherapeutic agent from solution comprises changing the pH of thesolution of the therapeutic agent.
 19. The method of claim 13 whereinthe step of removing the therapeutic agent from solution compriseschanging the ionic strength of the solution of the therapeutic agent.20. A method for making a medical device comprising: (a) providing astructure comprising a porous material; (b) immersing the structurecomprising a porous material in a saturated solution of a therapeuticagent for a sufficient period of time to allow the solution to fill theporous material; (c) removing the medical device from the solution; (d)drying the medical device; and (e) repeating steps (b) through (d) toprovide a therapeutic agent dispersed within the porous material. 21.The method of claim 20 further comprising a step of removing air bubblesfrom the porous material while being immersed in the solution of thetherapeutic agent.
 22. The method of claim 21 wherein the step ofremoving air bubbles from the porous material comprises applyingultrasonics, reduced pressure, elevated pressure, or a combinationthereof, to the solution.
 23. The method of claim 20 wherein the medicaldevice is a A stent.
 24. The method of claim 23 wherein the stent has aporous polymeric film thereon.
 25. The method of claim 23 furthercomprising a step of applying an overlayer of a polymer.